Treatment of stereotypic, self-injurious and compulsive behaviors in man and animals using antagonists of NMDA receptors

ABSTRACT

NMDA receptor antagonists can be used in methods of treatment, for reducing the frequency of stereotypic behaviors in animals and for reducing the frequency of analogous compulsive behaviors in humans, for example, those that have been said to be a manifestation of, or related to, obsessive-compulsive disorder. Of particular interest are the (+) enantiomers of opioid receptor binding compounds, which can reduce the frequency of the behaviors, while having no effects from binding at the opioid receptor.

RELATED APPLICATION

This application is a divisional of U.S. application Ser. No. 09/262,546filed Mar. 4, 1999, now U.S. Pat. No. 6,242,456, which claims thebenefit of U.S. Provisional Application No. 60/077,312 filed Mar. 9,1998, the entire teachings of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Stereotypic behavior in animals (also called “repetitive” or“compulsive” behavior) has been defined by some researchers as acts thatare repetitive and constant, which may appear to serve no obviouspurpose, and may even be injurious. One of the most common of thesebehaviors is, for example, crib-biting by horses—grabbing and biting ofthe feed bin or of parts of the structure in which the horse is housed(also called “cribbing”—see U.S. Pat. No. 4,692,451 for a description ofthis behavior, associated behaviors, and resulting problems). Anothercommon behavior in dogs is compulsive licking of itself—even to thepoint of aggravating a sore (“lick granuloma” or “acral lick”).Stereotypies may show some degree of variation, and may be unlike themore typical behaviors such as cribbing and licking, in that they haveno features of repetitive motion, but are characterized rather bymotionless staring or a frozen body position.

The repetitive behaviors of animals and the compulsive behaviors ofhumans have both responded to treatment with some of the same drugs.See, e.g., regarding treatment of acral lick with drugs that have shownbenefit in human obsessive-compulsive disorder (OCD), Rapoport, J. L.,Clin. Neurophar. 15: Suppl. 1 Pt A: 261A-262A, 1992; Rapoport, J. L. etal., Arch. Gen. Psychiatry 49:517-521, 1992. See also Smith, K. C. andPittlekow, M. R., J. Am. Dermatol. 20:860-861, 1989, wherein it wasreported that onychophagia and skin picking responded to treatment with(−) enantiomers of opioid antagonists, which have been effective also incompulsive hair pulling in cats, feather picking in birds, acral lick indogs and cribbing in horses (Dodman, N. H., Vet. International 6:13-20,1994; Dodman, N. H. et al., J. Am. Vet. Med. Assoc. 193:815-819, 1988;Turner, R., Proceedings of Annual Conference of the Association of AvianVeterinarians: Aug. 31-Sep. 4, 1993, Nashville, Tenn., pp. 116-118). Seealso U.S. Pat. No. 4,692,451, the contents of which are incorporatedherein by reference in their entirety. Studies of this type providejustification for the conclusion that the same underlying physiologicalprocesses are involved in causation of the animal and human behaviors.Therefore, they should all respond positively to new methods of therapy.

SUMMARY OF THE INVENTION

The invention relates to a method for treating a disorder in animals,variously termed repetitive, stereotypic, or compulsive behavior, andwhich can also be self-injurious by administering to the animal, by oneor more appropriate routes and by appropriate doses, an effective amountof one or more NMDA receptor antagonists. In some cases, the compositioncomprises one or more NMDA receptor antagonists that are nothaloperidol. In some cases the composition comprises one or more NMDAreceptor antagonists, and does not comprise an opioid receptor agonistor antagonist which is primarily (−) enantiomer. In some cases thecomposition comprises one or more NMDA receptor antagonists, but doesnot comprise an opioid receptor agonist or antagonist of either (+) or(−) enantiomer.

The invention, more particularly, is a method for treating compulsivebehaviors in horses, such as crib biting, wind sucking, stall walking,weaving, head bobbing, pawing, tonguing, self-biting, flank sucking, andhead shaking, by administering to the horse a composition comprising oneor more NMDA receptor antagonists.

In another particular embodiment, the invention is a method for treatingcompulsive behaviors in dogs, such as compulsive licking (acral lick),tail chasing and whirling, pacing, fly chasing, shadow or light chasing,excessive barking, stone eating, excessive drinking, and excessiveeating, comprising administering to the dog an effective amount of anNMDA receptor antagonist.

Also an embodiment of the invention is a method for treating compulsivebehaviors in cats, such as wool sucking, compulsive licking, tailchasing, hoarding, pacing, excessive marking, compulsive masturbation,and compulsive aggression.

A further embodiment of the invention is a method for treatingcompulsive behaviors in birds, such as feather and skin picking.

The invention relates to a method for treating a disorder (or more thanone disorder, as it is possible that two or more can occur together) inhumans, variously termed repetitive, stereotypic, or compulsivebehavior, and which can also be self-injurious, by administering to thehuman, by one or more appropriate routes and by appropriate doses, oneor more NMDA receptor antagonists, thereby relieving the frequencyand/or intensity of the compulsion and reducing the frequency and/orintensity of the behavior.

Examples of the human behaviors which can be treated by these methodsinclude, but are not limited to: obsessive-compulsive disorder (with itsvarious manifestations of checking, counting, washing to removecontamination, etc.), trichotillomania, psychogenic excoriation, nailbiting, compulsive exercising, smoking compulsion, drug (opioid)addiction, and alcohol addiction. These compulsive behaviors may berelated also to compulsive gambling, compulsive shopping, and eatingdisorders.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph in which cumulative crib-bites per time afteradministration of D-methadone (diamonds), as well as the rate ofcrib-bites per 5-minute interval (squares) are plotted, showing theeffect of D-methadone on the rate of compulsive crib-biting in horses.

FIG. 2 is a bar graph in which the cumulative number of turns of thestall in 30 minutes are plotted for a stall-walking horse observedbefore and after the injection of dextromethorphan.Dextromethorphan-HBr, 1.0 mg/kg i.v., was injected after 60 minutes ofcontrol observations. “Saline” indicates the number of turns by thehorse, observed in 30 minutes after injection of saline. “Dextro”indicates the number of turns by the horse, observed in 30 minutes afterinjection of dextromethorphan.

FIG. 3 is a bar graph showing the time spent in three typical behaviorsin four experiments in which the effect of dextromethorphan on ashadow-chasing dog was tested on four consecutive days. Back-slashhatching indicates “searching”; forward-slash hatching indicates“fixated ”, white indicates “resting.” Dextromethorphan-HBr, 2 mg per kgp.o. was administered twice daily, and testing was carried out one hourafter the morning dose. Bars indicate the total time of each of threebehaviors during the first 10 minutes after the beginning of testing.Time not accounted for was spent in moving about the room, usually outof range of the camera.

FIG. 4 is a graph of the cumulative number of scratches by a mouse,plotted at 10 minute intervals, when naltrexone (10 mg/kg; squares),dextromethorphan (10 mg/kg; triangles), or no compound (control;diamonds) was injected into the mouse 10 minutes before injection ofcompound 40/80.

FIG. 5A is a graph of the cumulative number of scratches by a mouse,plotted at 10 minute intervals, when haloperidol (2.0 mg/kg; triangles),dextromethorphan (20 mg/kg; squares), +or naloxone (20 mg/kg; diamonds),or saline (control; X's) was injected into the mouse 30 minutes afterinjection of compound 40/80.

FIG. 5B is a graph of the cumulative number of scratches by a mouse,plotted at 10 minute intervals, when (+) methadone (5.0 mg/kg; squares),(+) methadone (10 mg/kg; triangles), or saline (control; diamonds) wasinjected into the mouse 30 minutes after injection of compound 40/80.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to methods of treating animals displaying varioustypes of repetitive and/or compulsive (frequently also calledstereotypic) behaviors using compounds that are characterizable as NMDAreceptor antagonists (having specific binding activity to NMDA receptorsand/or the ability to block activation of the NMDA ligand-gated channelby an activating compound).

Compulsive or stereotypic behaviors in dogs can be put into severalcategories. “Grooming behaviors” can include, for example, lickgranuloma (acral lick), compulsively licking objects, self-scratching,chewing feet, hair and nails, etc., flank sucking and air licking.“Locomotory behaviors” can include, for example, running and jumping,pacing, head shaking, paw shaking, tail swishing, freezing, whirling,tail chasing, walking in a pattern, as along a fence, digging and floorscratching. “Vocalization behaviors” include, for example, rhythmicbarking, growling or snarling at self, barking at food, crying andhowling. “Predatory behaviors” include, for instance, staring, airbatting, jaw snapping, pouncing, prey chasing or searching, ducking, andfly chasing. “Eating and drinking behaviors” include, for example,excessive drinking, polyphagia, excessive drooling, gravel and dirteating, stone chewing, wool sucking, and eating fabrics. “Sexualbehaviors” include, for example, compulsive mounting. See, for tablescompiling the observed behaviors of not only cats and dogs, but alsohorses, primates and other species Dodman, N. H., “Veterinary Models ofObsessive-Compulsive Disorder,” Chapter 16, pp. 319-334 InObsessive-Compulsive Disorders: Practical Management (M. A. Jenike etal., eds.), Moseby, Boston, 1998. See also N. H. Dodman et al.,“Veterinary Models of OCD,” Chapter 6, pp. 99-143, InObsessive-Compulsive Disorders: Diagnosis, Etiology and Treatment, (E.Hollander et al., eds.), Marcel Dekker, New York, 1997. See also Tables1 and 2 in Luescher, U. A. et al., “Stereotypic or Obsessive-CompulsiveDisorders in Dogs and Cats,” In Veterinary Clinics of North America:Small Animal Practice 21(2): 401-413 (March, 1991).

Cats can exhibit behaviors similar to those seen in dogs, with the mostcommon behaviors being those related to grooming, such as excessiveself-licking and hair chewing. Other repetitive behaviors are tailchasing, hoarding, wool sucking, pacing, excessive marking, compulsivemasturbation, and compulsive aggression.

Horses have not been observed to display compulsive predatory behaviors,but can also suffer from species-typical compulsive behaviors, such ascribbing, wind sucking, stall walking, weaving, head bobbing, pawing,lip flapping/tonguing, head shaking, flank biting, trichotillomania, andmasturbation.

Birds, especially those of the order Psittaci, which includes parakeets,cockatoos, lories, macaws, and South American and African parrots, aresubject to compulsive behaviors, particularly feather pulling and skinpicking, but also route tracing, spot picking, masturbation andregurgitation.

Compulsive behaviors exhibited by animals of the porcine species includebar biting, vacuum chewing, and chain chewing.

Animals of the ovine and bovine species can exhibit behaviors similar tothose seen in other species. These include tonguing and compulsivesucking, weaving, hair licking, and masturbation.

Bears in captivity have developed pacing behaviors.

Primates in captivity have been observed to have the followingcompulsive behaviors: hair pulling and skin picking (categorized as“grooming” behaviors), self sucking, licking and chewing (“consummatory”behaviors), self-directed aggression (“aggressive” behavior),masturbation and rectal probing (sexual behaviors), and bouncing inplace and somersaulting (locomotory behaviors).

Humans, as would be expected, have developed a great variety ofcompulsive behaviors, compared to those of the animals. Common humanbehaviors include: paraphilias (sexual); self-directed aggression andpyromania (aggressive); checking, avoidance of contamination (fear andavoidance); skin/nose picking, trichotillomania (grooming); gambling,hoarding (“predatory”); whirling, tics, compulsive exercising(locomotor); and binge eating (consummatory). This list, like the listsof behaviors of the animals given above, is not intended to be completeor limiting, as variations with each individual animal or human arepossible. Further descriptions of human compulsive behaviors can befound in Diagnostic and Statistical Manual of Mental Disorders(DSM-IV™), American Psychiatric Association, 1994.

Stereotypic animal behaviors have been compared to obsessive-compulsivedisorder and disorders involving similar repetitive or compulsivebehaviors in humans. As Freud described compulsive behavior, “thepatient is impelled to perform actions which not only afford him nopleasure but from which he is powerless to desist.” It has beenhypothesized that a more satisfactory definition of stereotypies orcompulsive behaviors would encompass both the animal and humansyndromes, by being based on common, specific neuropathologicdifferences in the brains of animals or humans manifesting thesebehaviors, compared to animals or humans that do not manifest suchbehaviors. See discussion in Luescher, U. A. et al., “Stereotypic orObsessive-Compulsive Disorders in Dogs and Cats,” In Veterinary Clinicsof North America: Small Animal Practice 21(2): 401-413 (March 1991).

The similarities have led some to refer to not only the human behaviors,but also the animal behaviors, as “compulsive” behaviors or“obsessive-compulsive disorders.” See Overall, K. L., Canine Practice17:39-42, 1992; Dodman, N. H. and B. Olivier, CNS Spectrums 1(2): 10-15,1996. It has been proposed that acral lick in dogs, and compulsive barbiting and chain chewing of tethered sows, as well as several otherbehaviors of animals, might serve as useful models of humanobsessive-compulsive disorder (Dodman, N. H. and B. Olivier, CNSSpectrums 1(2): 10-15, 1996). Compulsive self-grooming behaviors inanimals, in particular, have been compared with trichotillomania inhumans (Moon-Fanelli, A. A. et al., Chapter 3, pp. 63-92 InTrichotillomania, (D. J. Stein et al., eds.), American PsychiatricPress, Inc., Washington, D.C. The serotonin reuptake inhibitorcitalopram has been found to be useful in the treatment of OCD andpossibly compulsive hair-pulling in humans, and has been usedsuccessfully, in the majority of the dogs in the study reported, totreat acral lick dermatitis (Stein, D. J. et al, Depression and Anxiety8:39-42, 1998). These data provide evidence that acral lick dermatitiscan be a useful animal analog of OCD.

Similarities that can be observed among the repetitive animal behaviors,and between the repetitive behaviors of animals and the repetitivebehaviors of humans, suggest a common etiology. In addition, there arestudies that link one human syndrome to another. Neurologic disorderssuch as epilepsy, Sydenham's chorea, and toxic and vascular lesions ofthe basal ganglia have been found concurrently with OCD (Freeman, J. etal., Paediatrics 35:42-49, 1965; Kettle, P. and I. Marks, Br. J.Psychiatry 149:315-319, 1989), leading to the suggestion that repetitivebehaviors may be a sign of acquired disease. Observation of increasedrates of OCD in Tourette syndrome (TS) patients, increased prevalence oftics and TS in OCD patients, and the increased familial rates of OCD andTS in first-degree relatives of both TS and OCD probands lead to theconclusion that there is a genetic association between the two disorders(Leonard, H. L., et al., Am. J. Psych. 149:1244-1251, 1992; Leonard, H.L., et al., Adv. Neurol. 58:83-93, 1992). A study of the incidence ofOCD in the first degree relatives of trichotillomania patients found ahigher lifetime prevalence of OCD in this group than in the relatives ofnormal controls (Lenane, M. C. et al., J. Child Pyschol. Psychiatry33(5): 925-933, 1992). Attention deficit/hyperactivity disorder occursfrequently with Tourette syndrome (see, for example, Harris, E. L. etal., J. Int. Neuropsychol. Soc. 1(6): 511-516, 1995).

N-methyl-D-aspartic acid (NMDA) selectively activates a major subclassof glutamatergic excitatory amino acid receptors in the vertebratecentral nervous system (CNS). The NMDA receptor is a ligand-gatedchannel that is activated by the coagonists glutamate (or selectively invitro by NMDA) and glycine acting at a strychnine-insensitive glycinesite (Wong, E. H. F. and J. A. Kemp, Annu. Rev. Pharmacol. Toxicol31:401-425, 1991). It is further subject to regulation by avoltage-dependent block of the channel by Mg²⁺, a voltage-independentaction of Zn²⁺, the redox state of the receptor, arachidonic acid,ethanol, neurosteroids, pH and polyamines.

Although the exact structure of NMDA receptors is still a matter ofdebate, NMDA-sensitive ionotropic glutamate receptors probably consistof tetrameric, heteromeric, subunit assemblies that have differentphysiological and pharmacological properties and are differentiallydistributed throughout the central nervous system. The NMDA receptorsare positively modulated by glycine, by polyamines (spermine andspermidine), by histamine and, under some conditions, by cations. NMDAreceptors are coupled to glutamate-gated high conductance channelspermeable to K⁺, Na⁺, and Ca⁺⁺, that are critical for long-termpotentiation, and are selectively activated by the artificial glutamateanalog N-methyl-D-aspartate. There is evidence that NMDA receptors playan important role in learning and in other phenomena in the brain, suchas drug dependence and addiction, chronic pain, and CNS development, aswell as in normal or disturbed synaptic transmission in some areas ofthe CNS. See, for review on NMDA receptors, Danysz, W. and Parsons, C.G., Pharmacological Reviews 50(4): 597-664, 1998.

An NMDA receptor antagonist is any one of a number of agents which hasbeen shown to bind to NMDA receptors and/or block any of the sites thatbind glycine, glutamate, NMDA or phencyclidine (PCP). Blocking the NMDAreceptor sites has the effect of preventing the creation of an actionpotential in the cell. NMDA receptor antagonists include those compoundsthat preferentially bind to NMDA receptors, but may also have otheractivities.

NMDA receptor antagonists include the following: previously identifiedcompetitive and non-competitive antagonists of NMDA receptors, which maybind, for instance, at the glycine site (on the NR1 subunit) and/or atthe glutamate recognition site (on the NR2 subunit). Preferred NMDAreceptor antagonists are those that have the ability to cross theblood-brain barrier and also demonstrate a low incidence of sideeffects. Such NMDA receptor antagonists can include, for example,compounds known as arylcyclohexylamines such as the anesthetic ketamine,neuroleptics such as haloperidol (Coughenour, L. L. and J. J. Corden, J.Pharmacol. Exp. Ther. 280:584-592, 1997) and the anti-Parkinson drugamantadine. Ifenprodil and eliprodil are neuroprotective agents whosemechanism of action has been attributed to their NMDA antagonistproperties (Scatton, B. et al., pp. 139-154 In Direct and AllostericControl of Glutamate Receptors, Palfreyman, M. G. et al., eds., CRCPress, 1994). Trifluperidol and haloperidol have been shown to have asimilar selectivity for the NR1a NR2B receptor subtype expressed inXenopus oocytes (Ilyin, V. et al., Soc. Neurosci. Abstracts 21:835,1995. Memantine, felbamate, ifenprodil, eliprodil, CGS19755, remacemide,and CNS 1102 are also antagonists of NMDA receptors (Lipton, S. A. andP. A. Rosenberg, New England Journal of Medicine 330 (9): 613-622,1994). A large number of NMDA receptor antagonists have been synthesizedand tested for interaction with the NMDA receptor complex, and researchinto the synthesis and improvement of NMDA receptor antagonists iscontinuing. See, for example, U.S. Pat. No. 5,783,700, WO 97/10240, U.S.Pat. No. 5,710,168, WO 98/03189, and DE 19601782.

NMDA receptor antagonists also include newer preparations underdevelopment e.g., CP 101, 606 (Di, X. et al., Stroke 28:2244-2251, 1997)BIII CL (Grauert, M. et al., J. Pharmacol. Exp. Ther. 285:767-776,1998); AR-RI5896AR (Palmer, C. G. et al., J. Pharmacol. Exp. Ther.288:121-132, 1999) LY274614 (Tiseo, P. J. and Inturrisi C. E., J.Pharmacol. Exp. Ther. 264:1090-1096, 1993); and NMDA antagonists thatact on the glycine B site (Danysz, W. and C. G. Parsons, Pharmacol. Rev.50:597-664, 1998).

Many different types of assays, with many variations of each type, havebeen used by those of skill in the art to test compounds for theproperties of an NMDA receptor antagonist. Triton-treated membranefractions prepared from rat telencephalon (including cortex,hippocampus, and striatum) can be used in binding assays to determineK_(D)'s of compounds; the effects of various compounds on [³H]glycinebinding can be determined, yielding a K_(i), (Kessler, M. et al., J.Neurochem 52:1319-1328, 1989). Ebert, B. et al. (Eur. J. Pharmacol. Mol.Pharmacol. 208:49-52, 1991) have described assays that determine K_(i)values of compounds by evaluating their affinities to membrane fractionsisolated from various parts of the rat brain. It was found that the testcompounds showed markedly lower affinity for the MK-801 binding sites inthe rat cerebellum compared to MK-801 binding sites in the cortex(approximately 25-fold lower). K_(D) values were similar for rat cortex,hippocampus, striatum, midbrain and medulla pons, although B_(max)values (indicating density of binding sites) for these tissues variedconsiderably.

In other types of tests of compounds for properties of NMDA receptorantagonists, onset and relief of block of NMDA-induced voltage-clampedneuron currents can be measured after application of a compound(Mealing, G. A. R. et al, J. Pharmacol. Exp. Ther. 288:204-210 (1999);Mealing, G. A. R. et al., J. Pharmacol. Exp. Ther. 281:376-383 (1997)).Trapping of block by NMDA antagonists has been studied by a methoddescribed also in Mealing, G. A. R. et al., J. Pharmacol. Exp. Ther.288:204-210 (1999) and in Blanpied, T. A. et al., J. Neurophysiol.77:309-323 (1997), measuring current amplitudes on rat cortical neurons.Tests of the effectiveness of NMDA receptor antagonists asantinociceptive agents are the rat tail-flick test and the formalintest, both described in Shimoyama, N. et al., J. Pharmacol. Exp. Ther.283:648-652 (1997). Other assays for NMDA receptor binding and effectsof this binding are referred to in the review by Danysz and Parsons,Pharmacological Reviews 50(4): 597-664, 1998.

Preferred NMDA receptor antagonists are those which have a K_(D) in anNMDA receptor binding assay greater than 10 μM and less than or equal to100 μM, more preferred are those NMDA receptor antagonists which have aK_(D) greater than 1 μM and less than or equal to 10 μM, even morepreferred are those NMDA receptor antagonists which have a K_(D) greaterthan 100 nM and less than or equal to 1 μM, still more preferred arethose NMDA receptor antagonists which have a K_(D) greater than 10 nMand less than or equal to 100 nM, and most preferred are those NMDAreceptor antagonists which have a K_(D) equal to or less than 10 nM.

There is evidence for three major categories of opioid receptors in thecentral nervous system. These have been designated μ, κ, and δ. Bindingto the opioid receptors can be measured in assays such as thosedescribed in Kristensen, K. et al., Life Sciences 55(2):PL45-PL50(1994), using bovine caudate nucleus. Opioid receptor binders (which acteither as an agonist or antagonist) are those compounds that bind toopioid receptors with a dissociation constant of less than about 100 nM.Preferably, opioid receptor binding molecules bind to opioid receptorswith a K_(D) of less than 10 nM. A given opioid drug may interact to avariable degree with all three types of receptors and act as an agonist,partial agonist, or antagonist, at each type of receptor. The antagonistnaloxone binds with high but variable affinity to all of thesereceptors. The term “naloxone-sensitive” is sometimes used synonymouslywith “opioid” in describing the actions of a given compound. See Jaffe,J. H. and W. R. Martin, “Opioid Analgesics and Antagonists,” pp. 485-521In The Pharmacological Basis of Therapeutics (A. G. Gilman et al.,eds.), 8th ed., Pergamon Press, New York, 1990.

Compounds classified as opioids have the ability to bind to opioidreceptors. These can be natural or synthetic compounds. It has beenfound that some opioids tested for binding to the NMDA receptor are NMDAreceptor antagonists (Ebert, B. et al, Biochemical Pharamacology56:553-559, 1998). Within the class of compounds that are opioids andare NMDA receptor antagonists is a subset of compounds that can exist as(−) and (+) forms. Where the enantiomers have been tested for bindingaffinity to NMDA receptors, both have been found to have bindingactivity; for some of these compounds, the (+) enantiomer has beendemonstrated as having a higher affinity for NMDA receptors (Gorman, A.L., et al., Neurosci. Lett. 223:5-8, 1997; Choi, D. W. and V. Viseskul,Eur. J. Pharmacol. 155:27-35, 1988; Craviso, G. L. and Musacchio, J. M.,Molec. Pharmacol. Exp. Ther. 264:1090-1096, 1993).

While Applicants do not wish to be bound by a single mechanism of actionof the methods of the claims, one hypothesis that explains the resultsobserved in the Examples is that both narcotic agonists and narcoticantagonists can bind to NMDA receptors and act as antagonists of NMDAreceptors. Support for this hypothesis can be found in the scientificliterature: (1) narcotic agonists and antagonists bind to NMDA receptors(see study of inhibition of binding of [³H]dextromethorphan in Craviso,G. L. and J. M. Musacchio, Molec. Pharmacol. 23:629-640, 1983); (2) both(+) and (−) enantiomers can bind to NMDA receptors, with the (+)enantiomer in most cases having a higher affinity for the NMDA receptor(see Craviso, G. L. and Musacchio, J. M. Molec. Pharmacol. 23:629-640,1983); also see study of inhibition of binding of MK-801 to NMDAreceptors in synaptic membranes from rat forebrain in Gorman, A. L. etal., Neurosci. Lett. 223:5-8, 1997); (3) like compounds previouslycharacterized as NMDA antagonists, narcotic agonists and antagonists canprotect cultured neurons from glutamate toxicity (Choi, D. W. andViseskul, V. Eur. J. Pharmacol. 155:27-35, 1988).

Assuming that both (+) and (−) enantiomer of narcotic antagonistsdecrease stereotypic behaviors by blocking NMDA receptors, there areconsiderable advantages to be gained by employing (+) enantiomers. Theseare: (1) there is no induction of narcotic receptors; (2) narcotics canbe employed for pain relief if necessary (e.g. oral surgery or othersurgery), as (+) enantiomers of narcotic antagonists do not blocknarcotic analgesia. The (+) enantiomers, unlike some known NMDAantagonists, readily cross the blood brain barrier. They do not producetoxic side effects like dizocilpine (MK-801). There is much experiencewith dextromethrophan as an anti-tussive with very little toxicity.Furthermore, there is considerable experience in treating addiction with(−) naltrexone and with racemic methadone. Toxicity of these substancesis minimal.

Substituting (+) methadone for racemic methadone or (−) acetyl-lmethadol in the treatment of narcotic addicts would have manyadvantages, including: 1) decreased craving without maintainingaddiction; 2) no tolerance, and therefore lower doses; 3) no problemswith security or drug diversion; and 4) less difficulty in weaningaddicts. Block of NMDA receptors should also decrease craving forcocaine and alcohol (Sass, H. et al., Arch. Gen. Psychiarty 53:673-680,1996; Mitchem, L. D. et al., Pharmacol. Biochem. Behavior 62:97-102,1999).

Preferred compounds to be used in the treatment of repetitive behaviordisorders include (+) enantiomers of both natural and synthetic opioids,such as dextromethorphan, dextrorphan, (+) methadone and (+)pentazocine; (+) enantiomers of synthetic narcotic antagonists such as(+) naloxone, (+) naltrexone, (+) nalmefene, and (+) diprenorphine.

Compositions to be used in methods described herein for the treatment ofstereotypic, self-injurious and compulsive behaviors in animals and inhumans include those comprising NMDA receptor antagonists; thosecompositions comprising NMDA receptor antagonists, wherein thecomposition does not comprise haloperidol; those compositions comprisingNMDA receptor antagonists, wherein the composition does not comprisehaloperidol, and wherein the composition does not comprise primarily (−)enantiomer of an opioid receptor agonist or antagonist; compositionscomprising NMDA receptor antagonists, wherein the composition does notcomprise haloperidol, and wherein the composition does not comprise anopioid receptor agonist or antagonist as (−) or (+) enantiomer; also,compositions comprising a compound selected from the group consistingof: dextromethorphan, dextrorphan, naltrexone, naloxone, methadone,pentazocine, nalmefene, diprenorphine, nalorphine, hydromorphone,oxymorphone, hydrocodone, oxycodone, buprenorphine, butorphanol,nalbuphine, fentanyl, metazocine, cyclazocine, etazocine, and acombination of any of the preceding, wherein the compounds arepredominantly (+) enantiomer.

Further compounds which can be used, preferably topically, in acomposition for the treatment of behaviors such as psychogenicexcoriation and scratching associated with pruritus are compounds suchas loperamide, MK-801, and ketamine, wherein the compound is primarily(+) enantiomer, of those that are optically active.

Animals to be treated for repetitive behaviors include, but are notlimited to, birds and mammals, for example, captive “wild” birds andmammals, such as those living in zoos or animal preserves, especiallyspecies that are predatory or can be predatory, such as feline, canineand ursine species, domestic animals, such as those raised for meat orfurs (e.g., chickens, pigs, cattle, minks), and those animals kept aspets or for recreational purposes, such as rats, mice, cats, dogs,horses, and various types of birds, such as parrots, cockatoos,parakeets, pigeons and the like.

“Horses” as used herein includes those domesticated animals that areusually called “horses,” but also those animals that are sometimesclassified by size as being ponies or miniature horses.

“Of an equine species” refers herein not only to horses, donkeys, andthe like but also to equine hybrids, such as mules and hinnies.

Similarly, “of a canine species” refers herein not only to domesticdogs, but also to wild dogs and canine hybrids.

Stereotypic movement disorder of humans is characterized by “repetitive,seemingly driven, and nonfunctional motor behavior (e.g., hand shakingor weaving, body rocking, head banging, mouthing of objects,self-biting, picking at skin or bodily orifices, hitting own body).” Theseverity of the behavior is such that it interferes with normalactivities or results in bodily injury if preventive measures were notused. Self-injurious behaviors occur in certain medical conditionsassociated with mental retardation (e.g., fragile X syndrome, de Langesyndrome, and Lesch-Nyhan syndrome, characterized by self-biting). Seepages 118-121 In Diagnostic and Statistical Manual of Mental Disorders(DSM-IV™), American Psychiatric Association, 1994.

Smoking compulsion in humans is the urge to perform the act of smoking(tobacco cigarettes, cigars, or tobacco contained in another vessel orvehicle). The act of smoking is the physical manipulation of thecigarette or other tobacco vehicle and the conscious control ofbreathing that is normally performed in the course of taking in andblowing out the tobacco smoke, primarily involving the hands and mouth,in a kind of ritual. Smoking compulsion usually accompanies thewell-documented nicotine addiction resulting from frequent and habitualtobacco smoking, but can be thought of as a compulsion which is separatefrom the craving satisfied by the administration of nicotine by a routeother than smoking. This compulsion to smoke may be responsible for thefailure of the simple administration of decreasing doses of nicotine (bytransdermal patch or by nicotine-containing chewing gum, for example) towean smokers from their smoking habit.

Psychogenic excoriation (also sometimes referred to as neuroticexcoriation or pathologic skin picking) is a human disordercharacterized by excessive scratching, picking, gouging, or squeezingthe skin, and occurs in approximately 2% of dermatology clinic patients,mostly female (Gupta, M. A. et al., Compr. Psychiatry 27:381-386, 1986).It has been hypothesized that psychogenic excoriation is an impulsecontrol disorder which is related to obsessive-compulsive disorder, orwhich is a manifestation of obsessive-compulsive disorder (McElroy, S.L. et al., J. Clin. Psychiatry 55:33-53, 1994). Patients withpsychogenic excoriation have responded to serotonin reuptake inhibitorssuch as fluoxetine and sertraline (Gupta, M. A. and A. K. Gupta, Cutis51:386-387, 1993; Stein, D. J. et al., Psychosomatics 34:177-181, 1993;Phillips, K. A. and S. L. Taub, Psychopharmacol. Bull. 31:279-288, 1993;Kalivas, J. et al, Arch. Dermatol. 132:589-590, 1996). In a study offluvoxamine (a selective serotonin reuptake inhibitor used in thetreatment of OCD) for the treatment of psychogenic excoriation, patientsshowed significant improvement (Arnold, L. M. et al., Journal ofClinical Psychopharmacology 19:15-18, 1999).

In what can also be considered a related self-injurious behavior,scratching associated with pruritis has been shown to respond toperipherally acting opiates, such as loperamide (U.S. Pat. No.5,849,761; U.S. Pat. No. 5,849,762). An animal model, using injectionsof a chemical irritant, can be used to test the effectiveness of agentsto treat scratching associated with pruritis (Kuraishi, Y. et al.,European Journal of Pharmacology 275: 229-233, 1995).

An effective amount of an agent, a compound or a drug is an amount thatproduces a measurable improvement in the condition to be treated (e.g.,a reduction in the frequency of the behavior exhibited in the human oranimal, compared to the frequency of behaviors exhibited in a human oranimal left untreated or sham-treated).

A compound primarily in the (+) form can be from greater than 50% to100% (+) enantiomer. Similarly, a compound that is primarily (−) can befrom greater than 50% (in a racemic mixture) to 100% (−) enantiomer.Compositions comprising primarily the (+) form of an opioid can havegreater than 50% to 60% (+) enantiomer, but preferably have greater than60% to 70% (+) enantiomer, more preferably greater than 70% to 80% (+)enantiomer, still more preferably greater than 80% to 90% (+)enantiomer, and most preferably, more than 90% (+) enantiomer.

Agents to be used in methods of treating a human or an animal for arepetitive and/or compulsive behavior disorder can be employed incombination with a non-sterile or sterile carrier or carriers for usewith cells, tissues or organisms, such as a pharmaceutical carriersuitable for administration to a human or animal subject. Suchcompositions comprise, for instance, a media additive or atherapeutically effective amount of an agent and a pharmaceuticallyacceptable carrier or excipient. Such carriers may include, but are notlimited to, saline, buffered saline, dextrose, water, ethanol,surfactants, such as glycerol, excipients such as lactose andcombinations thereof. The formulation can be chosen by one of ordinaryskill in the art to suit the mode of administration. The chosen route ofadministration will be influenced by such factors as the solubility,stability and half-life of the agent, for instance.

Agents to be used in the treatment of a repetitive and/or compulsivebehavior disorder may be employed alone or in conjunction with othercompounds, such as other therapeutic compounds. The pharmaceuticalcompositions may be administered in any effective, convenient manner,including administration by topical, oral, anal, vaginal, intravenous,intraperitoneal, intramuscular, subcutaneous, intranasal, transdermal orintradermal routes, among others. In therapy or as a prophylactic, theactive agent may be administered to a subject as an injectablecomposition, for example as a sterile aqueous dispersion, preferablyisotonic, or “packaged” as liposomes or microspheres.

When injectable compositions are desired, the functional antagonists ofthe present invention may be formulated, for example, into preparationsfor injection by dissolving, suspending or emulsifying them in anaqueous or non-aqueous solvent, such as vegetable oil, syntheticaliphatic acid glycerides, esters of higher aliphatic acids or propyleneglycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives.

Alternatively, if one wishes to prepare an oral dosage form containingone of the functional antagonists herein encompassed, commonly used andpharmaceutically acceptable tableting excipients, such as lactose,microcrystalline cellulose, corn starch, stearic acid, or the like, maybe used, if desired, to prepare such dosage forms.

Alternatively, the composition may be formulated for topicalapplication, for example, in the form of ointments, creams, lotions, eyeointments, eye drops, ear drops, mouthwash, impregnated dressings andsutures and aerosols, and may contain appropriate conventionaladditives, including, for example, preservatives, solvents to assistdrug penetration, and emollients in ointments and creams. Such topicalformulations may also contain compatible conventional carriers, forexample cream or ointment bases, and ethanol or oleyl alcohol forlotions.

In addition, the amount of the compound will vary depending on the size,age, body weight, general health, sex, and diet of the host, and thetime of administration, the biological half-life of the compound, andthe particular characteristics and symptoms of the disorder to betreated. Adjustment and manipulation of established dose ranges are wellwithin the ability of those of skill in the art, and preferably minimizeside effects and toxicity.

Exemplification

EXAMPLE 1

Treatment of Cribbing in Horses

Horses were admitted to the Large Animal Hospital of Tufts UniversitySchool of Veterinary Medicine or were tested in their home barn.Cribbing straps and food were removed prior to testing. Control rates ofcrib-biting were observed and recorded for 5 minute intervals for onehour or more after an intravenous injection of 0.15 M saline. Test drugswere administered orally (by gavage) or by injection into the jugularvein. Solutions were made up with physiological saline and sterilized byfiltration through a 0.2 micron filter (Millipore).

For the experimental data shown in FIG. 1, after establishment of astable control rate of approximately 10 crib-bites per minute, 50 mg ofD-methadone-HCl in 25 ml saline was injected i.v. In FIG. 1, thecumulative number of crib-bites was plotted against time as was the rateper 5 minute interval (Shuster, L. and N. H. Dodman, pp. 185-202, InPsychopharmacology of Animal Behavior Disorders, (N. H. Dodman and L.Shuster, eds.), Blackwell Scientific, Malden, Mass., 1998). The ratedecreased between the second and the fifth 5-minute interval followinginjection. The control rate then resumed during the next 80 minutes ofobservation. Horses were observed continuously during scoring for sideeffects that might be attributed to the treatment. These includedchanges in posture, disposition and motor activity. See also Table 1.

EXAMPLE 2

Treatment of Stall-Walking in Horses

Dextromethorphan-HBr, 1.0 mg/kg i.v., was injected after 60 minutes ofcontrol observations, to test its effect on a stall-walking horse. Whenmeasuring “stall walking” locomotor activity, each circuit around thestall was scored as one rotation. Cumulative rotations per 5 minuteinterval were plotted against time to establish the rate of circling.The results of the experiment are plotted in FIG. 2. See also Table 1.

TABLE 1 Effect of some Drug Treatments on the Rate of Crib BitingCrib-biting Frequency Number number per per minute minute DurationBefore After Horse Drug Dose & Route of Effect treatment treatment CB(−) naloxone 65 min. 12 0.1 .04 mg/kg, i.v. (10 min lag) CB (+) naloxone60 min. 10 6.6 0.12 mg/kg, iv. (30 min lag) CB (+) naloxone 60 min. 9.20.8 0.18 mg/kg, i.v. (no lag) CB Dextromethorphan 90 min 8 1.7 1.0mg/kg, p.o. (35 min lag) CB Dextromethorphan 35 min 7.6 0.3 1.0 mg/kg,i.v. (no lag) CB (+) Methadone 20 min 8.8 2.6 0.2 mg/kg, iv. (10 minlag) CB (+) Methadone 10 min 8.2 5.5 .01 mg/kg, iv. CB ketamine 50 min8.2 1.3 0.2 mg/kg, iv. (no lag) Frito Dextromethorphan 100 min  3.5 1.83.2 mg/kg p.o. (30 min lag) Full Circle Dextromethorphan 45 min 3.5turns .3 turns (turning) 1.0 mg/kg,. iv. (no lag) per min. per min.

EXAMPLE 3

Treatment of Light/Shadow-Chasing in Dogs

Behavior of a shadow-chasing dog was filmed with a video camera for 10minutes after the onset of testing in the owner's home. To stimulate thedog, the owner moved around a flashlight beam on the floor for 5seconds. The typical response after the light was turned off was franticsearching for the light followed by fixed staring at the floor.Dextromethorphan-HBr, 2 mg per kg p.o. was administered twice daily andtesting was carried out one hour after the morning dose. Results areshown in FIG. 3.

EXAMPLE 4

Mouse Model for Pruritus

The animals used were BALB/c male mice, weighing 27-33 g. One mouse wasused per compound tested, except for two control mice receiving saline;two different mice were tested with (+) methadone, each with a differentdose. Compound 48/80 (Kuraishi, Y. et al., European Journal ofPharmacology 275:229-233, 1995), 0.5 mg/ml in saline, was injectedsubcutaneously in a volume of 0.1 ml, between the shoulder blades of themouse. Test compounds, dissolved in saline, were injectedintraperitoneally in a volume of 0.1 ml per 10 g, either 10 minutesbefore or 30 minutes after injection of compound 48/80. The cumulativenumber of scratches with a hind leg were recorded at 10 minute intervalsfor 60 minutes following the injection of compound 48/80. See Tables 2and 3, as well as FIGS. 4, 5A and 5B, showing the effectiveness of thecompounds tested: naltrexone, dextromethorphan, (+) methadone,haloperidol, and (+) naloxone.

TABLE 2 Effect of NMDA Blockers on Pruritus in Mouse: BlockerAdministered 10 Minutes Before 48/80 Cumulative Scratches TimeNaltrexone Dextromethorphan Minutes Control 10 mg/kg 10 mg/kg 10 5 0 120 52 0 57 30 166 0 105 40 277 1 157 50 364 61 182 60 498 73 192 (+)methadone Time 10 mg/kg Control 10 0 3 20 0 79 30 0 99 40 0 227 50 0 40460 0 456

TABLE 3 Effect of NMDA Blockers on Pruritus in Mouse: CompoundAdministered 30 Minutes After 48/80 Cumulative Scratches (+) (+) Meth-Metha- (+) Dextrometh- Halo- adone done 10 Naloxone orphan peridol TimeSaline 5 mg/kg mg/kg 20 mg/kg 20 mg/kg 2.0 mg/kg 10  4  0  6  4  47  220  70  56  38  48 125  87 30 134 114 106 105 158 108 40 181 145 107 112171 137 50 220 210 107 146 178 137 60 297 267 107 175 185 142

All references cited herein not previously specifically stated as beingincorporated by reference are hereby incorporated by reference in theirentirety.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention as defined by the appended claims.

What is claimed is:
 1. A method for treating obsessive-compulsivedisorder in a human, comprising administering to the human an effectiveamount of a composition comprising one or more NMDA receptorantagonists.
 2. The method of claim 1 wherein the NMDA receptorantagonist is (+) methadone.
 3. The method of claim 1 wherein thecomposition comprising one or more NMDA receptor antagonists has a K_(D)in an NMDA receptor binding assay greater than 10 μM and less than orequal to 100 μM.
 4. The method of claim 1 wherein the compositioncomprising one or more NMDA receptor antagonists has a K_(D) in an NMDAreceptor binding assay greater than 1 μM and less than or equal to 10μM.
 5. The method of claim 1 wherein the composition comprising one ormore NMDA receptor antagonists has a K_(d) in an NMDA receptor bindingassay greater than 100 nM and 1ess than or equal to 1 μM.
 6. The methodof claim 1 wherein the composition comprising one or more NMDA receptorantagonists has a K_(D) in an NMDA receptor binding assay greater than10 nM and less than or equal to 100 μM.
 7. The method of claim 1 whereinthe composition comprising one or more NMDA receptor antagonists has aK_(D) in an NMDA receptor binding assay loss than or equal to 10 nM. 8.The method of claim 1 wherein the composition does not comprisehaloperidol.
 9. The method of claim 1 wherein the obsessivc-compulsivedisorder is manifested by one or more behaviors selected from the groupconsisting of checking, counting and washing to remove contamination.10. The method of claim 1 wherein the composition further comprises apharmeceutical carrier.
 11. A method for treating obsessive-compulsivedisorder in a human, comprising administering to the human an effectiveamount of a composition comprising one or more NMDA receptorantagonists, wherein the composition does not comprise primarily (−)enantiomer of an opioid receptor agonist or antagonist.
 12. The methodof claim 11 wherein the NMDA receptor antagonist is (+) methadone. 13.The method of claim 11 wherein the composition comprising one or moreNMDA receptor antagonists has a K_(D) in an NMDA receptor binding assaygreater than 10 μM and less than or equal to 100 μM.
 14. The method ofclaim 11 wherein the composition comprising one or more NMDA receptorantagonists has a K_(D) in an NMDA receptor binding assay greater than 1μM and less than or equal to 10 μM.
 15. The method of claim 11 whereinthe composition comprising one or more NMDA receptor antagonists has aK_(D) in an NMDA receptor binding assay greater than 100 nM and lessthan or equal to 1 μM.
 16. The method of claim 11 wherein thecomposition comprising one or more NMDA receptor antagonists has a K_(D)in an NMDA receptor binding assay greater than 10 nM and less than orequal to 100 nM.
 17. The method of claim 11 wherein the compositioncomprising one or more NMDA receptor antagonists has a K_(D) in an NMDAreceptor binding assay less than or equal to 10 nM.
 18. The method ofclaim 11 wherein the composition does not comprise haloperidol.
 19. Themethod of claim 11 wherein the obsessive-compulsive disorder ismanifested by one or more behaviors selected from the group consistingof checking, counting and washing to remove contamination.
 20. Themethod of claim 11 wherein the composition further comprises apharmeceutical carrier.
 21. A method for treating obsessive-compulsivedisorder in a human, comprising administering to the human an effectiveamount of a composition comprising one or more compounds selected fromthe group consisting of: dextromethorphan, dextrorphan, naltrexone,naloxone, methadone, pentazocine, nalmefene, diprenorphine, nalorphine,hydromorphone, oxymorphone, hydrocodone, oxycodone, buprenorphine,butorphanol, nalbuphine, fentanyl, metazocine, cyclazocine, etazocine,and a combination of any of the preceding, wherein the compounds arepredominantly (+) enantiomer.
 22. The method of claim 21 wherein thecompound is methadone.
 23. The method of claim 21 wherein the compoundis dextromethorphan.
 24. The method of claim 21 wherein the compound isdextrorphan.
 25. The method of claim 21 wherein the compound isnaltrexone.
 26. The method of claim 21 wherein the compound is naloxone.27. The method of claim 21 wherein the compound is nalmefene.
 28. Themethod of claim 21 wherein the obsessive-compulsive disorder ismanifested by one or more behaviors selected from the group consistingof checking, counting and washing to remove contamination.
 29. Themethod of claim 21 wherein the composition comprises greater than 50% to60% (+) enantiomer.
 30. The method of claim 21 wherein the compositioncomprises greater than 60% (+) enantiomer
 31. The method of claim 21wherein the composition comprises greater than 70% (+) enantiomer. 32.The method of claim 21 wherein the composition comprises greater than80% (+) enantiomer.
 33. The method of claim 21 wherein the compositioncomprises greater than 90% (+) enantiomer.
 34. The method of claim 21wherein the composition further comprises a pharmeceutical carrier. 35.The method of claim 22 wherein the methadone is (+) methadone.
 36. Amethod for treating obsessive-compulsive disorder in a human, comprisingadministering to the human an effective amount of a compositioncomprising one or more NMDA receptor antagonists, wherein thecomposition does not comprise an opioid receptor agonist or an opioidreceptor antagonist.
 37. The method of claim 36 wherein the compositioncomprising one or more NMDA receptor antagonists has a K_(D) in an NMDAreceptor binding assay greater than 10 μM and less than or equal to 100μM.
 38. The method of claim 36 wherein the composition comprising one ormore NMDA receptor antagonists has a K_(D) in an NMDA receptor bindingassay greater than 1 μM and less than or equal to 10 μM.
 39. The methodof claim 36 wherein the composition comprising one or more NMDA receptorantagonists has a K_(D) in an NMDA receptor binding assay greater than100 nM and less than or equal to 1 μM.
 40. The method of claim 36wherein the composition comprising one or more NMDA receptor antagonistshas a K_(D) in an NMDA receptor binding assay greater than 10 nM andless than or equal to 100 nM.
 41. The method of claim 36 wherein thecomposition comprising one or more NMDA receptor antagonists has a K_(D)in an NMDA receptor binding assay less than or equal to 10 nM.
 42. Themethod of claim 36 wherein the obsessive-compulsive disorder ismanifested by one or more behaviors selected from the group consistingof checking, counting and washing to remove contamination.
 43. Themethod of claim 36 wherein the composition further comprises apharmaceutical carrier.